The NIH ALPS group currently follows a cohort of over 400 families. In the past we have described biomarkers for ALPS related to mutations in FAS (both germline and somatic) based on teh evaluation of 562 ALPS patients and their family members. This revealed that a level of double negative T cells above 4% together with an elevation of soluble FasL, Vitamin B12 or IL-10 has up to 98% of predictive value for ALPS with both germline and somatic FAS mutations. The results were incorporated into the new diagnostic criteria for ALPS. More recently we found that most mutations affecting the extracellular region of FAS disrupt protein function by inducing haploinsufficiency, with consequent low FAS expression, low DISC formation and suppressed apoptosis. These defects were milder as compared to mutations affecting the intracellular domains of FAS, potentially explaining the variable expressivity and lower penetrance seen in patients with mutations in the extracellular domains. During this reporting period we have collaborated with NIAID ALPS group assembled the first comprehensive clinical and laboratory report based on long term follow-up of 150 ALPS patients and over 60 mutation positive relatives to develop the most comprehensive long term report of the outcome in patients with ALPS as well as in those who harbor the same mutations but have little or no autoimmune symptoms. This work has defined the risk of lymphoma as almost a log higher than previously recognized. In addition, the use of splenectomy to control cytopenias has clearly identified as significantly increasing the risk of bacterial sepsis and a cause of death in a subgroup of these surgically managed patients. Importantly, many post-splenectomy patients have recurrence of their hematologic autoimmunity. Finally, this work has also identified that approximately 40% of mutation positive members of ALPS families have little or no clinical disease suggesting that other genetic and or environmental circumstances have a significant impact on the clinical outcome of individual patients.